Methods and Devices for Renal Nerve Blocking

ABSTRACT

Methods for treating a hypertensive human patient are disclosed herein. A method in accordance with one embodiment comprises delivering a neuromodulatory agent to a renal nerve of the patient via an intravascularly positioned drug delivery catheter. The method includes at least partially blocking neural activity along the renal nerve with the neuromodulatory agent, which results in a therapeutically beneficial reduction in blood pressure of the patient.

RELATED APPLICATIONS

This application is related and claims priority to the followingcommonly-owned applications: Ser. No. 60/408,665, entitled “Renal NerveStimulation Method And Apparatus For Treatment Of Patients” that wasfiled in the U.S. Patent and Trademark Office (USPTO) on Apr. 8, 2003and provisional application Ser. No. 60/370,190, entitled “Modulation OfRenal Nerve To Treat CHF”, that was filed in the U.S. Patent andTrademark Office (USPTO) on Apr. 8, 2002; Ser. No. 60/415,575 entitled“Modulation Of Renal Nerve To Treat CHF”, that was filed in the USPTO onOct. 3, 2002, and Ser. No. 60/442,970 entitled “Treatment Of RenalFailure And Hypertension”, that was filed in the USPTO on Jan. 29, 2003.The entirety of each of these applications is incorporated by referenceherein.

FIELD OF THE INVENTION

This invention relates to devices and methods for local drug delivery,and in particular is directed to an implantable system for targeteddelivery of a nerve blocking agent to the periarterial space of therenal artery for the purpose of blocking the renal nerve plexus, methodsfor implanting same, and methods and devices for treating diseases. Theinvention directs the nerve-blocking agent towards the nerve, preventsdissipation of the agent in the surrounding tissue and provides fixationof the drug delivery mechanism in the surrounding tissue.

BACKGROUND OF THE INVENTION

Hypertension (HTN) and congestive heart failure (CHF) are the mostimportant problems in contemporary cardiology. These chronic diseasesaccount for most cardiovascular morbidity and mortality, and, despitemuch progress, remain therapeutic challenges. The cornerstone of therapyfor both HTN and CHF includes the use primarily oral and intravenousdrugs acting directly or indirectly on the kidney, such as angiotensinconverting enzyme (ACE) inhibitors and diuretics, with the amount ofeach drug used dependent on the stage of the disease. While drug therapyis effective in the earliest stages of HTN and CHF, there is no trulyeffective drug treatment for the mid-to-later stages of these diseases.

HTN and CHF have many different initial causes. Irrespective of initialcause, both diseases follow a common pathway in their progression toend-stage disease, primarily as the result of excessive activity of therenal nerve. It has been shown in accepted animal models that renaldenervation can control HTN and improve symptoms and slow down theprogression of CHF. However, no drug or device therapies currently existthat can provide long-term, clinically usable blocking of renal nerveactivity in humans. The only available clinical method of renaldenervation is an invasive surgical procedure, technically difficult andof limited use, as the nerve quickly regenerates.

Of particular significance for this invention is the CHF condition thatdevelops in many patients following a myocardial infarction (MI).Coronary artery disease causes approximately 70% of congestive heartfailure. Acute MI due to obstruction of a coronary artery is a commoninitiating event that can lead ultimately to heart failure. This processby which this occurs is referred to as remodeling and is described inthe text Heart Disease, 5th ed., E. Braunwald, Ch. 37 (1997). Remodelingafter a myocardial infarction involves two distinct types of physicalchanges to the size, shape and thickness of the left ventricle. Thefirst, known as infarct expansion, involves a localized thinning andstretching of the myocardium in the infarct zone. This myocardium can gothrough progressive phases of functional impairment, depending on theseverity of the infarction. These phases reflect the underlyingmyocardial wall motion abnormality and include an initial dyssynchrony,followed by hypokinesis, akinesis, and finally, in cases that result inleft ventricular aneurysm, dyskinesis. This dyskinesis has beendescribed as “paradoxical” motion because the infarct zone bulgesoutward during systole while the rest of the left ventricle contractsinward. Consequently, end-systolic volume in dyskinetic hearts increasesrelative to nondyskinetic hearts.

The second physical characteristic of a remodeling left ventricle is theattempted compensation of noninfarcted region of myocardium for theinfarcted region by becoming hyperkinetic and expanding acutely, causingthe left ventricle to assume a more spherical shape. This helps topreserve stroke volume after an infarction. These changes increase wallstress in the myocardium of the left ventricle. It is thought that walltension is one of the most important parameters that stimulate leftventricular remodeling. In response to increased wall tension or stress,further ventricular dilatation ensues. Thus, a vicious cycle can result,in which dilatation leads to further dilatation and greater functionalimpairment. On a cellular level, unfavorable adaptations occur as well.This further compounds the functional deterioration.

Takashi Nozawa et al reported the effects of renal denervation in“Effects of long-term renal sympathetic denervation on heart failureafter myocardial infarction in rats” published in Heart Vessels (2002)16:51-56 Springer-Verlag. In rats the bilateral renal nerves weresurgically denervated (cut) (RD) two days before MI was induced bycoronary artery legation. Four weeks later, left ventricular (LV)function and sodium excretion were determined. In MI rats, RD improvedthe reduced sodium excretion. MI RD rats revealed lower LV end-diastolicpressure and greater maximum dP/dt as compared with those of MIinnervation (INN) rats. LV end-diastolic and end-systolic dimensionswere significantly smaller and LV fractional shortening was greater inMI RD rats than in MI INN rats.

Inventors described novel methods and devices for reversible minimallyinvasive modulation of the renal nerve in copending applications. Thisapplication describes novel drug delivery methods and integratedphysiological drug delivery and sensing systems that provide asignificantly more effective method of blocking the renal nerve for thepurpose of treating HTN and CHF than are currently available. Theobjective of this invention is a fully implantable device that blocksrenal nerve activity of at least one kidney that 1) can be placed in aminimally invasive manner and 2) requires minimal intervention by thepatient and physician; and will greatly increase patient complianceleading to a higher overall effectiveness of these therapies. Inaddition, to HTN and CHF, this method may be applicable to other majordiseases such as slowing the progression of chronic renal failure andreducing the number of patients requiring chronic hemodialysis.

Nerve blocking in humans is known and practiced mostly in the field oflocal anesthesia and pain control. While compounds utilized as generalanesthetics reduce pain by producing a loss of consciousness, localanesthetics act via a loss of sensation in the localized area ofadministration in the body. The mechanism by which local anestheticsinduce their effect, while not having been determined definitively, isgenerally thought to be based upon the ability to locally interfere withthe initiation and transmission of a nerve impulse, e.g., interferingwith the initiation and/or propagation of a depolarization wave in alocalized area of nerve tissue. The actions of local anesthetics aregeneral, and any tissue where nerve conduction, e.g., cell membranedepolarization occurs can be affected by these drugs. Thus, nervoustissue mediating both sensory and motor functions can be similarlyaffected by local anesthetics. Neurotoxins are the chemicals that whenapplied to nerve tissue in extremely small amounts can block a nerve fora period of time that significantly exceeds that achieved with localanesthetics. They are also more toxic and potentially more dangerous tothe patient than local anesthetics.

Different devices and formulations are known in the art foradministration of local anesthetics. For example, local anesthetics canbe delivered in solution or suspension by means of injection, infusion,infiltration, irrigation, topically and the like. Injection or infusioncan be carried out acutely, or if prolonged local effects are desired,localized anesthetic agents can be administered continuously by means ofa gravity drip or infusion pump. Thus, local anesthetics such asbupivacaine have been administered by continuous infusion, e.g., forprolonged epidural or intrathecal (spinal) administration. For prolongedcontrol of pain fully implantable pumps have been proposed andimplemented. These pumps can store a certain amount of drug and aphysician periodically refills those. Several authors proposed drugeluding implants for control of pain and muscle spasms that slowlyrelease an anesthetic agent at the site of implantation.

The duration of action of a local anesthetic is proportional to the timeduring which it is in actual contact with the nervous tissues.Consequently, procedures or formulations that maintain localization ofthe drug at the nerve greatly prolong anesthesia. Local anesthetics arepotentially toxic, both locally and via systemic absorption, yet must bepresent long enough to allow sufficient time for the localized pain tosubside. Therefore, it is of great importance that factors such as thechoice of drug, concentration of drug, and rate and site ofadministration of drug be taken into consideration when contemplatingtheir use for the application to block renal nerve. Charles Berde in“Mechanisms of Local Anesthetics” (Anesthesia, 5th addition, R. D.Miller, editor, Churchill-Livingstone, Philadelphia 2000, pp. 491-521)stipulated that only 1-2% of the total amount of local anesthetic, whendelivered by traditional methods, ever reaches the nerve. The rest ofthe drug is dissipated by circulation of blood that takes the drug away,not towards the nerve. It is therefore the purpose of this invention tomaximize the amount of drug directed towards the nerve so as to achievethe effective blockade of the renal nerve with the minimal amount ofdrug.

Theoretically, a suitable commercially available implantable drug pumpsuch as a Syncromed pump made by Medtronic Inc. (Shoreview, Minn.) canbe used to block the renal nerve in a human. The pump can deliver commoncommercially available solution of a local anesthetic agent such asbupivacaine to the tissue surrounding the renal nerve via an attachedcatheter. Although feasible, such embodiment of the renal nerve blockwill have practical limitations. To block a peripheral nerve (forexample, for the purpose of a commonly performed brachial plexus block)using conventional techniques the physician typically infiltrates 10-50ml of bupivacaine or similar anesthetic into the tissue surrounding thetargeted nerve. This usually achieves adequate blocking of both sensoryand motor signals for 2 to 6 hours. Commercially available bupivacainemarketed as Marcaine or Sensorcaine is available in concentrations of0.25 to 0.1%. For peripheral (single nerve) blocks concentrations of 0.5to 0.75% are typically used. There are several reasons why localanesthetics are so diluted. An amino-amide compound such as bupivacainecan be toxic both locally (it is an irritant) and systemically (itdepresses the heart). It is generally perceived that a local anestheticwill not be effective below certain minimum concentration and will betoxic above certain maximum concentration.

Implantable drug pumps are commonly equipped with an internal drugstorage reservoir of 30 to 50 ml. Bigger reservoirs are possible butimpose severe limitations on the physical and clinical acceptability ofthe implant. If the continuous. (24 hour a day 7 days a week) block ofthe patient's renal nerve is desired, and a conventional peripheralnerve blocking technique is used, the implanted pump reservoir will needto be refilled every day or even more frequently. This is possible butnot practical, since refilling of the pump is associated with the skinpuncture, causing pain and leading to the risk of local and systemicinfection. Also, daily infusion of a large amount of drug can result ina serious risk to the patient's health, especially if the patient has aweak heart. Notably the same drug bupivacaine is effective in a muchlower doze when delivered directly to the targeted nerve tissue in thepatient's spine. For example, an effective intrathecal (spinal) painblock can be achieved with 2-5 ml of bupivacaine. This observation showsthat more targeted delivery of the same drug to the nerve tissue canresult in 10 times or more reduction of the amount of drug needed fornerve blocking.

It is therefore the purpose of this invention to provide novel methodsand implantable devices that will effectively block renal nerve bytargeting the delivery of the selected drug to the nerve, reducingdissipation of the drug into the surrounding tissue, reducing the amountof drug stored in the device and increasing the time interval betweenthe refilling or replacement of the device. It is also the purpose ofthis invention to enable testing of the effectiveness of the renal nerveblockade and to perform the renal block automatically, intermittentlyand/or periodically in the clinical scenarios where the continuous blockis not desired.

SUMMARY OF THE INVENTION

Surgical denervation of the kidney in experimental animals suggestedmultiple immediate and long-term benefits for patients with cardiac andrenal diseases. The most significant potential beneficial effects are:slowing of the progression of CHF, resolution of fluid overload in CHFby induction or enhancement of diuresis, reduction of remodeling after amyocardial infarct, reduction of hypertension and slowing of theprogression of chronic renal disease to dialysis. The benefits areachieved via the reduction of the systemic sympathetic tone causingvasoconstriction of blood vessels, reduction of the load on the heartand the direct effects of denervation on the kidney. Both single kidneydenervation and bilateral denervation have potential benefits. Surgicaldenervation has been previously performed in animals and in few humansto control pain. It requires a major surgery, and is ineffective in longterm, since renal nerves eventually grow back. Additionally, after thesurgical denervation, the renal nerve can re-grow in a pathological wayand can cause pain and other serious side effects. Since fibroticchanges at the site of denervation make repeat surgical denervationimpossible, patients face the possibility of the removal of the kidneyto control the pain.

The inventors suggest an alternative method of reducing or blocking therenal nerve activity in patients by minimally invasive renal nervemodulation. Renal nerve modulation is achieved by controlled infusion ofa nerve-blocking agent into the periarterial space of the renal arteryof the kidney. The periarterial space is the area surrounding the renalarteries and veins, extending from the aorta and vena cava to andincluding the area around the kidney itself. Since renal nerves followthe external surface of the renal artery, when an effectiveconcentration of the nerve-blocking agent is present in thisperiarterial space, the renal nerve activity is substantially reduced orstopped. Methods and devices for both continuous and intermittentperiodic blocking of the renal nerve are proposed. These methods anddevices provide effective, reversible nerve blocking for a clinicallyrelevant duration of time, while avoiding major surgery and irreparabledamage to the nerve that characterize the previously used surgicaldenervation.

The preferred embodiment devices can be implantable drug pumps or drugeluding implants. Both classes of local drug delivery devices are known.Implanted pumps have been successfully used previously for control ofpain by infusion of local anesthetics into the patient's spine.Implantable pumps range from simple reservoirs (ports) implanted underthe skin with an attached catheter to sophisticated microprocessordriven programmable devices similar to pacemakers. Drug eluding implantshave been used to deliver birth control agents and to prevent restenosisof coronary arteries.

Implanted pumps can also be refilled with drug without surgery using atransdermal port accessible with a needle, though it is preferable toextend the time between refillings to minimize pain and the risk ofinfection. The programmable implantable pump embodiment also has anadvantage of the periodic drug delivery that can be adjusted up or downusing a remote communication link. This is particularly significant intreatment of chronic diseases such as CHF where the continuous constantnerve blocking can result in adaptation (resting of the physiologic gainor compensation) and the loss of therapeutic effect.

Drug eluding implants work primarily by diffusion. Drug eluding implantsare advantageous in the treatment of a temporary condition such asinfarct expansion following acute MI where an implant that blocks thenerve for approximately 30 days and then dissolves on its own can be thebest embodiment of the invention.

SUMMARY OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 illustrates the patient treated with an implanted pump embodimentof the invention.

FIG. 2 illustrates the physiologic mechanisms of renal nerve modulation.

FIG. 3 illustrates anatomic positioning of the renal nerve blockingdevice.

FIG. 4 illustrates an implantable drug infusion pump with a catheterelectrode.

FIG. 5 illustrates the infusion of an anesthetic drug into the renalfatpad.

FIG. 6 illustrates a catheter with a cuff for distributed drug infusioninto the periarterial space.

FIG. 7 illustrates a bifurcated catheter for drug infusion into theperiarterial space.

FIG. 8 illustrates a coiled catheter for drug infusion into theperiarterial space.

FIG. 9 illustrates a drug eluding implant in the periarterial space.

FIG. 9A illustrates a drug eluding biodegradable material in theperiarterial space.

FIG. 10 illustrates a porous drug infusion catheter.

FIG. 11 illustrates a drug infusion catheter with tissue ingrowth.

FIG. 12 illustrates the drug infusion catheter that directs the drugtowards the renal nerve.

FIG. 13 illustrates the drug infusion catheter that overlaps the renalartery and directs the drug infusion towards the renal nerve.

FIG. 14 is a cross-sectional view of the catheter and artery shown inFIG. 13.

DETAILED DESCRIPTION OF THE INVENTION

For the proposed clinical use, the capability of the invention is toblock the sympathetic activity of the renal nerve of the kidney bycontrolled local delivery of a nerve-blocking agent with the goal ofimproving the patient's renal and cardiac function. Elements of theinvention are useful for blocking nerves for the purpose other thantreating cardiorenal disease and can be applied in other anatomiclocations.

A nerve blocking agent is a drug that reduces or blocks conduction ofsignals by renal nerves. The nerve blocking agents used can be selectedfrom different groups including (1) local anesthetics, (2) ketamine (awell known sedative with nerve blocking properties), (3) tricyclicantidepressants such as amitriptyline, (4) neurotoxins such astetrodotoxin and saxitoxin or (5) any other class or type of agent thattransiently or permanently, partially or completely alters nerveconduction. The terms nerve blocking agent and nerve blocking drug areinterchangeable.

Cardiorenal disease is defined as a condition, chronic or acute, thatinvolves both the heart and the kidney. Examples of cardiorenal diseasesare hypertension and CHF. Cardiorenal diseases are characterized by theelevated activity of the renal nerve.

For the purpose of this invention, the renal nerve is defined as a anyindividual nerve or plexus of nerves and ganglia that conducts a nervesignal to and/or from the kidney and is anatomically located on thesurface of the renal artery, parts of aorta where the renal arterybranches from the aorta and/or on branches of the renal artery. Therenal nerve generally enters the kidney in the area of the hilum of thekidney, but may enter in any location where a renal artery or branch ofthe renal artery enters the kidney.

Periarterial space is defined as the space immediately surrounding therenal arteries, renal veins and their branches between the aorta and thehilum of the kidney. The renal fat pad is defined as the adipose tissueor fat that fills the periarterial space and surrounds the renal artery,renal vein, renal nerves and the kidney itself. The renal fascia is thelayer of connective tissue that surrounds, envelopes and contains therenal artery, renal vein, renal fatpad and the kidney itself.

An implantable or implanted device (commonly termed an “implant”) is anartificial device fully enclosed in the patient's body. It issignificant that implants allow the natural skin of the patient to serveas a barrier against infection. An implant can be, for example, acomplex electromechanical pump, catheter and port or a drug-releasingpolymer. Implantation can be achieved by open surgery, minimallyinvasive surgery or a transcatheter intervention, whether extravascular,intravascular or combination of any of the above. During theimplantation procedure, a surgical instrument or catheter is used tocross the skin, penetrating into the patient's body. The implant ispositioned at the desired site and the pathway used to access the siteis closed. The site heals and the device is now fully implanted.

An implantable pump is an implantable device that is inserted under thepatient's skin and can be refilled using a transdermal needle access. Animplantable pump may have an integral catheter or can be equipped with aseparate catheter that delivers medication to the periarterial space.Depending on the desired treatment modality, a preferred implantablepump can be programmable, patient controlled or a constant rate device.

A drug eluding implant is a device that is fully implanted in the bodythat slowly eludes the nerve-blocking agent into the target space. Oneexample of such a space is the renal periarterial space. Another exampleis inside the renal capsule, or the virtual space between the kidneytissue and the fibrous sheath surrounding the kidney tissues itself.Drug eluding implants work by diffusion and can be biodegradable or not.An osmotic pump is also a drug eluding implant. Different matrixes thatserve to slow down the diffusion of the drug into a target space are allcalled drug eluding implants for the purpose of this invention. Theseinclude gels, patches, injectable microspheres, suspensions, solutionsor any other matrix that may hold sufficient drug to cause the intendedeffect.

FIG. 1 illustrates a patient 101 treated with the preferred embodimentof the invention. Patient has kidneys 103 and 104 that are bean shapedorgans 12 cm long, 6 cm wide, 3 cm thick located outside and behind theperitoneal cavity. Patient is equipped with an implantable drug pump 105implanted in the patient's side under the skin. The pump is equippedwith a drug delivery catheter 106 that terminates in the area of therenal artery 107 where the delivered drug is capable of blocking therenal nerve.

FIG. 2 illustrates the role of renal nerve activity in the progressionof chronic cardiac and renal diseases. Increased renal afferent (fromthe kidney to the brain) nerve activity 201 results in the increasedsystemic sympathetic tone 202 and vasoconstriction (narrowing) 203 ofblood vessels. Increased resistance of blood vessels results inhypertension 204. Hypertension is a major contributor to the progressionof chronic heart failure and renal failure as well as the acute eventssuch as strokes and myocardial infarcts. Increased renal efferent (fromthe brain to the kidney) nerve activity 205 results in further increasedafferent renal nerve activity, secretion of the renal hormone renin 206,and reduction of renal blood flow and the decreased water and sodiumexcretion by the kidney. Renin contributes to systemic vasoconstrictionof blood vessels 203. In combination these renal factors result in fluidretention 207 and increased workload of the heart thus contributing tothe further deterioration of the patient. It should be clear from theFIG. 2 that moderation of renal nerve activity will benefit patientswith heart, kidney and circulatory system (cardiorenal) diseases.

FIG. 3 illustrates a preferred embodiment of the invention using a CTscan (digital X-ray) image of a human body. The pump 105 is implantedunder the skin in the patient's back. The pump is equipped with thecatheter 106. Tip 304 of the catheter resides near the renal artery 107.In this example, the tip 304 is shown in the hilum 305 area of thekidney where the renal blood vessels (arteries and veins) enter and exitthe kidney. In clinical practice, the tip could reside in otherlocations within the renal periarterial space as long as the positionallows the spread of the nerve blocking agent to at least a sufficientarea of the nerve to achieve the required level of nerve blockade. Eachkidney has an outer convex surface and an indentation on the inner sidecalled the hilum. The hilum functions as a route of entry and exit forthe blood vessels, lymph vessels, nerves and ureters of the kidney.Renal nerves follow the renal artery 107 that connects the kidney 104 tothe aorta 301 shown in front of the spine 302. Kidney and renal vesselsare enclosed in fat and fascia made of connective tissues that do notshow well on this type of CT scan image.

It is significant that the catheter 106 can be introduced into theperiarterial space under the CT guidance without surgery. The spatialresolution of modern imaging modalities such as CT, CT Fluoroscopy,Ultrasound and MRI allows an interventional radiologist to position thecatheter within a millimeter from the renal artery of a human. Theprocedure is performed using a needle, an exchange guidewire and similartechniques commonly used in interventional radiology. The distal end ofthe catheter can be left outside of the body for the test period or theentire treatment if the treatment requires only a short duration. Later,if the renal nerve blocking therapy is clinically successful, animplanted pump or a simple subcutaneous port such as a commerciallyavailable Port-A-Cath device can be connected to the already implantedcatheter for repeat infusions of the nerve-blocking drug.

FIG. 4 illustrates a simplified design of an implantable programmabledrug infusion pump. The pump 105 in implanted in a pocket under thepatient's skin 401. All the mechanisms of the pump are enclosed in atitanium or polymer case 402. Drug is stored in the reservoir 403. Torefill the pump a needle 405 is used to puncture the skin and the pumpreservoir septum 406. Septum 406 is made of a material such as siliconthat seals after the puncture. Drug is displaced from the reservoir bythe compressed propellant 407. The propellant can be achlorofluorocarbon, butane or other similar compound. The propellantacts on the drug through the elastic diaphragm 408. Alternatively, thediaphragm can act as a spring or it can be acted upon by the spring todisplace the drug. The catheter 106 is in fluid communication with thereservoir 403. The propellant urges the drug from the reservoir into thecatheter and through the catheter to the site of delivery, in this case,periarterial space of the renal artery and the renal nerve. To controlthe release of the drug, a valve 408 is placed between the reservoir andthe catheter. The valve is normally closed. When it is forced open bythe pump electronic control circuitry 409 for a short duration of time,a bolus of drug is released from the pump to the renal nerve-blockingsite. The internal battery 411 supplies energy to the electronics andthe valve. The communication electronics 410 allows the physician toreprogram the pump altering the amount and frequency of drug delivery aswell as to interrogate the device. The communication electronics can bea radio-frequency RF link. All the elements described above are known tothe developers of implantable drug pumps.

Programmable implantable infusion devices (also called implantablepumps) that actively meter the drug into an associated drug deliverycatheter are described in the U.S. Pat. Nos. 4,692,147; 5,713,847;5,711,326; 5,458,631; 4,360,019; 4,487,603; and 4,715,852.Alternatively, implantable infusion devices can control drug delivery bymeans of a rate-limiting element positioned between the drug reservoirand the delivery catheter as described in the U.S. Pat. No. 5,836,935,or by only releasing drug from the reservoir upon application ofpressure to a subcutaneously positioned control device as described inU.S. Pat. Nos. 4,816,016 and 4,405,305. Implantable infusion deviceshave been used for intravenous, intraarterial, intrathecal,intraperitoneal, intraspinal and epidural drug delivery but not forperiarterial drug infusion.

Known infusion pumps described above can be used to block the renalnerve for the purpose of treating cardiac diseases but they lack certainfeatures needed in practical application. It is important for thephysician to be able to determine that the nerve is in fact effectivelyblocked. In pain control applications of local anesthetics, thedisappearance of the pain by itself is an indicator of an effectiveblock. There is no natural indication of the renal nerve activity thatcan be simply measured. To address that problem, the pump 105 isequipped with a test electrode 412 on the tip 304 of the catheter 106.The electrode can be a single ring or multiple electrodes made of aconductive metal such as gold, stainless steel or titanium. Theelectrode 412 is connected to the control circuitry of the pump 409 by aconductive wire 413 integrated inside the catheter body 106. Except forthe tip electrode 412 the wire is electrically insulated from thepatient.

To test the effectiveness of the renal nerve block the control circuitryinitiates an electric pulse to the electrode. To close the electriccircuit the metal case 402 of the pump can be used as a second returnelectrode. Alternatively the catheter 106 can be equipped with more thanone electrode. Low electric current pulse that can be in the range of5-10 milliamps is passed through the tissue surrounding the electrode412. If the nerve block is effective, patient will have no sensation oftingling or minor electric shock. If the block is ineffective, thenerves in the surrounding tissue will conduct the pulse, causing painthat the patient then reports to the physician and the physician will beable to make adjustments to therapy such as, for example, increase thedose of drug delivered by the pump.

This aspect is similar to the surgical technique used byanesthesiologists to establish short term invasive nerve blocks duringsurgery. Before the start of the surgery, the anesthesiologist places aneedle precisely on the nerve or plexus. To do this, a speciallydesigned electrical nerve stimulator is used. The nerve stimulatordelivers a very small electrical current, too small to be felt, to thenerve, which causes twitching of the particular muscles supplied by thatnerve or plexus of nerves. In this example, the nerve serves as nothingmore than a sophisticated “electrical wire”, which is now conducting thecurrent delivered by an electrical device to the muscles, in place ofthe normally conducted current originating from the brain. The patientwill therefore experience small muscle twitches in the muscles suppliedby that nerve similar to when your eye is twitching. This technique hasnever been previously applied to an implanted device. In the proposedinvention, the physician will be able to perform the nerve block test intheir office, without sophisticated surgical techniques and sterileenvironment. The external programmer device will initiate a commandsequence that will be received by the electronics of the implanted pumpusing RF waves.

In an alternate embodiment, the catheter can have two or more sets ofelectrodes, at least one set proximal to and at least one set distal tothe area of renal nerve blockade. Each set of electrodes is insufficient proximity to the renal nerve so that it can either senseintrinsic nerve activity or stimulate nerve activity. It is clear thatif the pump control circuitry initiates and electrical pulse to a oneset of electrodes on one side of the block and does not record acorresponding and appropriately timed signal on the opposite side of theblock, then the drug is effective in creating the nerve block.Conversely, if the electrical activity is sensed, more drug must beinfused to create the desired block. It is also clear that thisinformation can be used as feedback by the control circuitry toautomatically adjust the timing and/or amount of drug released.

FIG. 5 illustrates the anatomic placement of the drug infusion catheter106 in the periarterial space of the renal artery. Catheter 106 is shownschematically in connection to the implanted pump 105. The kidney 102 issupplied with blood by the renal artery 107 from the aorta 301. Theperiarterial space is defined as space immediately surrounding the renalarteries and veins along its length between the connection to the aortaand the hilum 305 of the kidney. The renal artery can branch into two ormore arteries. The renal vein and its branches connecting the kidney tothe vena cava of the patient share the space. These additional elementsof the renal vascular system are omitted on FIG. 5 and the followingfigures for clarity but are presumed there.

Renal nerve 501 is shown schematically as a branching network attachedto the external surface of the renal artery 107. Anatomically, the renalnerve forms one or more plexi on the external surface of the renalartery. Fibers contributing to these plexi arise from the celiacganglion, the lowest splanchnic nerve, the aorticorenal ganglion andaortic plexus. The plexi are distributed with branches of the renalartery to vessels of the kidney, the glomeruli and tubules. The nervesfrom these sources, fifteen or twenty in number, have a few gangliadeveloped upon them. They accompany the branches of the renal arteryinto the kidney; some filaments are distributed to the spermatic plexusand, on the right side, to the inferior vena cava.

A fibrous connective tissue layer, called the renal capsule, encloseseach kidney. Around the renal capsule is a dense deposit of adiposetissue, the renal fat pad, which protects the kidney from mechanicalshock. The kidneys and the surrounding adipose tissue are anchored tothe abdominal wall by a thin layer of connective tissue, the renalfascia. The periarterial space of the renal artery is externally limitedby renal fascia 502 that extends between the kidney and the aorta andcontains renal vessels and nerves. Renal fascia presents a naturalbarrier to the dissipation of the infused drug 504 that is emitted fromthe tip of the catheter 106. Fat fills the space between the fascia andthe renal artery. In particular, there is a fat tissue layer 503 in thehilum of the kidney that surrounds the renal pedicle where arteries,nerves and veins enter the kidney. The catheter tip 304 is shownpenetrating the renal fascia and the renal fat and the anesthetic drugis infused into the fatpad tissue. Although shown in the hilum of thekidney, the tip can be placed anywhere in the renal periarterial spaceas long as the position allows the spread of the nerve blocking agent toat least a sufficient area of nerve to achieve the required level ofnerve blockade. In practice, there is an advantage to placing the tip ata location in continuity with the periarterial space fat. Anestheticdrugs such as amino ester and amino amide local anesthetics such asbupivacaine have high lipid solubility. The invention takes advantage ofthis. A single bolus of bupivacaine, after being infused into theseareas, will be adsorbed by fat and retained at the location of the renalnerve. In this manner, the renal fat serves as storage of drug that willthen be slowly released from the renal fat, and in this way, obtains thedesired prolonged nerve blocking action.

FIG. 6 illustrates an alternative embodiment of the invention where thecatheter 106 has a sealed tip 601 but is equipped with multiple sideholes or pores 602 in the wall of the catheter. The pores can be assmall as a micron in diameter. Pores less than 20 microns in diameterwill allow penetration of the nerve-blocking drug through the wall ofthe catheter and into the periarterial space, renal fat pad andultimately to the renal nerve target. At the same time, these smallpores will discourage ingrowth of tissue into the side holes andincrease the probability of the catheter patency after being implantedin the body for a long time. This design helps redistribute theanesthetic in the periarterial space between the wall of the renalartery and the renal fascia 502. The catheter is equipped with a cuff603 to encourage ingrowth of connective tissue and prevents escape ofthe infused drug through the puncture in the renal fascia. The cuff canbe made of a natural or synthetic fiber material with pores larger than20 microns and preferably 100 microns. For example, Dacron cuffs arecommonly used in surgically implanted catheters for long term vascularaccess and dialysis in humans, Dacron cuffs support ingrowth of tissue,prevent dislodgment and provide a barrier to infection.

FIG. 7 illustrates an embodiment of the catheter 106 that bifurcates inthe periarterial space of the kidney after it enters inside the renalfascia. The internal lumen of the catheter is split between two or morebranches 701 and 702. Catheter brunches can have end holes; side holesor wall pores for the delivery of medication to the renal nerve.

FIG. 8 illustrates an embodiment of the catheter 106 that forms a coil801 inside the periarterial space. The coil can be equipped with sideholes or pores to evenly distribute the infused drug in the periarterialspace around the renal artery.

FIG. 9 illustrates an alternative preferred embodiment of the invention.The nerve blocking agent is stored in the drug eluding implant 901. Theimplant 901 is contained in the periarterial space after theimplantation surgery. Implant can be permanent or slowly biodegradable.Prior to implantation the implant is impregnated or “loaded” with anerve-blocking agent that is gradually released over time into theperiarterial space in the amount sufficient to block the renal nerve. Animplantable drug eluding implant or pellet(s) made of a nonbiodegradablepolymer has the drawback of requiring both surgical implantation andremoval. Use of a biocompatible, biodegradable implant overcomesdeficiencies of nonbiodegradable implants. A biodegradable implant canrelease a drug over a long period of time with simultaneous orsubsequent degradation of the polymer within the tissue intoconstituents, thereby avoiding any need to remove the implant. Adegradable polymer can be a surface eroding polymer. A surface erodingpolymer degrades only from its exterior surface, and drug release istherefore proportional to the polymer erosion rate. A suitable suchpolymer can be a polyanhydride. It is advantageous to have a surfaceeroding implant where the eroding surface faces the renal artery and therenal nerve. Other surfaces of the implant may be designed to erode at aslower rate or not erode at all that directing the drug towards therenal nerve target.

Implants for long-term drug delivery are known. For example, suchimplants have been used or proposed for delivering a birth control drugsystemically (into circulation) or a chemotherapeutic agent to alocalized breast tumor. Examples of such implantable drug deliverydevices include implantable diffusion systems (see, e.g., implants suchas Norplant for birth control and Zoladex for the treatment of prostatecancer) and other such systems, described of example in U.S. Pat. Nos.5,756,115; 5,429,634; 5,843,069. Norplant is an example of a class ofthe drug eluding implants also called controlled release systemscomprising a polymer for prolonged delivery of a therapeutic drug.Norplant is a subdermal reservoir implant comprised of a polymer can beused to release a contraceptive steroid, such as progestin, in amountsof 25-30 mg/day for up to sixty months. Norplant uses the DURINbiodegradable implant technology that is a platform for controlleddelivery of drugs for periods of weeks to six months or more. DURIN canbe adopted for delivery of an anesthetic into the periarterial space.The technology is based on the use of biodegradable polyesterexcipients, which have a proven record of safety and effectiveness inapproved drug delivery and medical device products. DURIN technology isavailable from the DURECT Corporation of Cupertino, Calif.

Drug eluding implants generally operate by simple diffusion, e.g., theactive agent diffuses through a polymeric material at a rate that iscontrolled by the characteristics of the active agent formulation andthe polymeric material. An alternative approach involves the use ofbiodegradable implants, which facilitate drug delivery throughdegradation or erosion of the implant material that contains the drug(see, e.g., U.S. Pat. No. 5,626,862). Alternatively, the implant may bebased upon an osmotically-driven device to accomplish controlled drugdelivery (see, e.g., U.S. Pat. Nos. 3,987,790, 4,865,845, 5,057,318,5,059,423, 5,112,614, 5,137,727, 5,234,692; 5,234,693; and 5,728,396).These osmotic pumps generally operate by imbibing fluid from the outsideenvironment and releasing corresponding amounts of the therapeuticagent. Osmotic pumps suitable for the renal nerve blocking applicationare available from ALZA Corporation of Mountain View, Calif. under thebrand name of Alzet Osmotic Pumps and the Duros implant. Duros implantis a miniature cylinder made from a titanium alloy, which protects andstabilizes the drug inside. Water enters into one end of the cylinderthrough a semipermeable membrane; the drug is delivered from a port atthe other end of the cylinder at a controlled rate appropriate to thespecific therapeutic agent. The advantage of drug eluding implants isthat they can store a common anesthetic agent in concentration muchhigher than that used for common local anesthetic injections. Accuratedelivery of small amounts of the drug via diffusion enables storage ofthe many months supply of the nerve-blocking agent in the implant andeliminates the need for frequent refills typical of an implanted drugpump. It is also clear that more than one drug can be released from theimplant, that function in either in a complementary or inhibitingmanner, to enhance or block the activity of each other.

FIG. 9A illustrates an alternative embodiment of the local drug eludingsystem illustrated by FIG. 9. In this embodiment the sustained releaseof the nerve-blocking agent is accomplished by infusing or implanting aself-forming biodegradable compound impregnated with the nerve-blockingagent in the periarterial space around the renal artery. Thenerve-blocking agent is delivered in a biodegradable matrix such as aninjectable get or microspheres. The action of the nerve-blocking drug isthus prolonged and can be enhanced by adding other medicaments, such assteroids, that suppress inflammation at the application site. Thisembodiment has an advantage of allowing better distribution andconformance of the drug eluding implant to the anatomic spacesurrounding the renal nerve. The carrier matrix loaded with the nerveblocking drug can be applied as a patch by the surgeon to the surface ofthe renal artery. Then the periarterial space will be closed and thefascia repaired. Alternatively the carrier matrix can be deliveredthrough a needle attached to an infusion device. Such needle can beinserted into the periarterial space under CT guidance as illustrated byFIG. 3. For delivery through a needle the matrix will need to be in theform of gel or injectable microspheres.

Patches and gels containing local anesthetics have been previously usedfor topical application to numb skin at the site of irritation or burnas well as for example during cataract eye surgery. One applicable gelis described in the U.S. Pat. No. 5,589,192 to Okabe, et al. “Gelpharmaceutical formulation for local anesthesia.”

Injectable microparticles or microspheres or microcapsules loaded withdrugs are also known. Injectable microspheres are made of degradablematerials, such as lactic acid-glycolic acid copolymers,polycaprolactones and cholesterol among others. For example, U.S. Pat.No. 5,061,492 related to prolonged release microcapsules of awater-soluble drug in a biodegradable polymer matrix which is composedof a copolymer of glycolic acid and a lactic acid. The injectablepreparation is made by preparing a water-in-oil emulsion of aqueouslayer of drug and drug retaining substance and an oil layer of thepolymer, thickening and then water-drying. In addition, controlledrelease microparticles containing glucocorticoid (steroid) agents aredescribed, for example, by Tice et al. in U.S. Pat. No. 4,530,840. Inanother embodiment, the implanted microspheres are stable and do notdegrade on their own. In this case, the microspheres are broken viaexternal, directed application of an energy source, such as ultrasound,temperature or radiation. Breaking of the microspheres release theencapsulated drug and provide the desired physiologic effect, in thiscase, nerve blockade.

U.S. Pat. No. 5,700,485 to Berde, et al. titled “Prolonged nerveblockade by the combination of local anesthetic and glucocorticoid”describes in sufficient detail methods of manufacturing and applicationof biodegradable controlled release microspheres for the prolongedadministration of a local anesthetic agent. The microspheres are formedof biodegradable polymers polyanhydrides, polylactic acid-glycolic acidcopolymers. Local anesthetics are incorporated into the polymer.Prolonged release is obtained by incorporation of a glucocorticoid intothe polymeric matrix or by co-administration of the glucocorticoid withthe microspheres. Significantly U.S. Pat. No. 6,238,702 to the sameauthors entitled “High load formulations and methods for providingprolonged local anesthesia” described the polymer matrix that containedsignificantly higher concentration of local anesthetic than is normallyused for injections. Since the periarterial space can anatomicallyaccommodate an implant of substantial size nerve blocking for at least30 days and more preferably several years is possible. U.S. Pat. No.5,618,563 to Berde, et al. titled “Biodegradable polymer matrices forsustained delivery of local anesthetic agents” further elaborates on thebiodegradable controlled release system consisting of a polymeric matrixincorporating a local anesthetic for the prolonged administration of thelocal anesthetic agent, and a method for the manufacture thereof.

FIG. 10 illustrates the design of the drug delivery catheter for theinvention that improves fixation of the catheter and distribution of theinfused drug in the periarterial space. After the implantation animplant and the surrounding tissue undergo changes. It is the purpose ofthis part of the invention to improve the interface of the drug deliverydevice to maximize the effect of the drug on the nerve while minimizingthe amount.

The human body acts spontaneously to reject or encapsulate any foreignobject, which has been introduced into the body or a specific bodilyorgan. In some cases, encapsulation will impede or halt drug infusion.In others, the delivery fluid will reflux from the tissue through aspace opened between the exterior of the catheter and the tissue of thebore in which the catheter is received. Either of these results willgreatly diminish the effect of direct infusion of medicaments onaffected body tissue. Thus, the body's own natural defense systems thustend to frustrate the procedure. The reaction of living tissue to animplant can take a number of different forms. For example, the initialresponse to the surgical trauma of implantation is usually called theacute inflammatory reaction and is characterized by an invasion ofpolymorphonuclear leukocytes (PMNs). The acute inflammatory reaction isfollowed by the chronic inflammatory reaction, which is characterized bythe presence of numerous macrophages and lymphocytes, some monocytes andgranulocytes. Fibroblasts also begin accumulating in the vicinity of theimplant and begin producing a matrix of collagen. The fibroblasts andcollagen form a connective tissue capsule around the implant and thechronic inflammatory cells to effectively isolate the implant and thesecells from the rest of the body. Connective tissue consisting of a finenetwork of collagen with active producing fibroblasts accompanied bychronic inflammatory cells, capillaries and blood vessels is referred tocollectively as granulation tissue.

Thus, when a material is implanted into a soft tissue bed of a livingorganism such as a human or an animal, a granulation tissue capsule isformed around the implant material consisting of inflammatory cells,immature fibroblasts and blood vessels. This tissue capsule usuallyincreases in thickness with time and contracts around the implant,deforming the implantation site, and possibly the implant itselfdepending upon the rigidity of the implant.

Implant illustrated by FIG. 10 is the tip 304 of the drug deliverycatheter 106 connected to the implanted drug pump explained earlier inthis application. The tip 304 is in the fluid communication with theinternal lumen 1001 of the catheter and is shown with an internal cavity1002 to which the nerve-blocking drug is delivered by the pump 104 (SeeFIG. 4). The tip is made out of the porous material, preferably a porousplastic such as for example PTFE. It is known that, when the implant isporous with pore entry diameters larger than approximately 20 microns,tissue grows into these pores. This phenomenon appears desirable to manymedical device application because it makes an implant one with theimplanted organ and in theory it allows tissue ingrowth into the implantand reduces capsular contraction. For example, U.S. Pat. No. 4,011,861to Enger discloses an implantable electric terminal which has porespreferably in the range of about 10 to 500 microns so that blood vesselsand tissue can grow into the pores.

The embodiment illustrated by FIG. 10 combines a material with smallpores, preferably less than 20 microns 304 designed to discourage thetissue ingrowth and a material with larger pores, preferably larger than20 microns 1004 to encourage tissue ingrowth. Material 1003 allows freediffusion and convection of the drug from the cavity 1002 to theperiarterial space. Material 1004 encourages the natural fixation of thecatheter tip 304 so that it will not be dislodged by motion and migrateout of the periarterial space.

FIG. 11 illustrates the catheter tip made of porous materials. It showsthe surrounding tissue 1101 ingrowth 1102 into the large pore implant1004 section. The small pore section 1003 is oriented to direct the druginfusion towards the renal artery 107 and the renal nerve 501.

FIG. 12 further illustrates an embodiment of the porous tip of thecatheter 106 for directional drug delivery. The portion of the implantthat surrounds the drug filled cavity 1002 and that is oriented awayfrom the renal nerve is made of the material 1004 that is impermeable todrug. Portion of the implant that is oriented towards the renal nerve(on the surface of the renal artery) 1003 is made of the material thatis permeable to the nerve blocking agent. Drug flux 1201 is shown asunidirectional therefore directing the therapy towards the site andminimizing the loss of the drug.

FIGS. 13 and 14 further illustrate an embodiment of the porous tip ofthe catheter 106 that at least partially encloses or envelopes the renalartery 107 with the intention of further directing the drug deliverytowards the renal nerve. The tip forms a multi-layer cuff around theartery. The outer shell 1004 of the cuff is made of the material that isimpermeable to the infused drug to prevent dissipation of the said drugaway from the renal nerve. The material 1004 can also have large poresto encourage ingrowth and fixation of the implant. The inner layer 1003is made of material permeable to the nerve-blocking drug. It is in fluidcommunication with the delivery catheter 106. The layer 1003 can beequipped with internal channels to facilitate equal distribution of drug1201 in the space 1301 between the cuff and the artery 107.

While the invention has been described in connection with what ispresently considered to be the most practical and preferred embodiment,it is to be understood that the invention is not to be limited to thedisclosed embodiment, but on the contrary, is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

1-23. (canceled)
 24. A method, comprising: delivering a neuromodulatoryagent to a renal nerve of a hypertensive human patient via anintravascularly positioned drug delivery catheter, wherein delivering aneuromodulatory agent to the renal nerve comprises delivering theneuromodulatory agent via an intravascular to extravascular approach;and at least partially blocking neural activity along the renal nervewith the neuromodulatory agent, wherein at least partially blockingneural activity along the renal nerve results in a therapeuticallybeneficial reduction in blood pressure of the patient.
 25. The method ofclaim 24 wherein delivering a neuromodulatory agent to a renal nerve ofa hypertensive human patient comprises positioning a needle within aperiarterial space of the patient and injecting the neuromodulatoryagent via the needle into the periarterial space of the patient.
 26. Themethod of claim 25 wherein positioning a needle within a periarterialspace of the patient comprises positioning the needle under CT guidance.27. The method of claim 25 wherein positioning a needle within aperiarterial space of the patient comprises positioning a distal tip ofthe drug delivery catheter within a target site in continuity with aperiarterial fat tissue layer surrounding a renal pedicle of thepatient.
 28. The method of claim 25 wherein positioning a needle withina periarterial space of the patient comprises positioning a distal tipof the drug delivery catheter within renal fascia of the patient. 29.The method of claim 24, further comprising intravascularly deliveringthe drug delivery catheter through an abdominal aorta to the renalartery of the patient before delivering the neuromodulatory agent. 30.The method of claim 29 wherein intravascularly delivering the drugdelivery catheter through an abdominal aorta to the renal arterycomprises intravascularly delivering the drug delivery catheter over aguidewire.
 31. The method of claim 24, further comprising removing thedrug delivery catheter from the patient after delivering theneuromodulatory agent to conclude the procedure.
 32. The method of claim24 wherein delivering a neuromodulatory agent via an intravascularlypositioned drug delivery catheter comprises intravascularly positioningthe drug delivery catheter within the renal artery under guidanceimaging.
 33. The method of claim 25 wherein intravascularly positioningthe drug delivery catheter within the renal artery under guidanceimaging comprises intravascularly positioning the drug delivery catheterwithin the renal artery under fluoroscopic guidance.
 34. The method ofclaim 24, further comprising determining whether neural activity alongthe renal nerve has been substantially blocked.
 35. The method of claim34 wherein determining whether neural activity has been substantiallyblocked comprises electrically stimulating the renal nerve and detectinga response in the patient.
 36. The method of claim 24, furthercomprising monitoring a parameter of the drug delivery catheter and/ortissue within the patient before and during delivery of theneuromodulatory agent.
 37. The method of claim 36, further comprisingaltering delivery of the neuromodulatory agent in response to themonitored parameter.
 38. The method of claim 24 wherein at leastpartially blocking neural activity along the renal nerve comprises atleast substantially blocking sympathetic neural activity along the renalnerve of the patient.
 39. The method of claim 24 wherein delivering aneuromodulatory agent to a renal nerve of a hypertensive human patientcomprises delivering a neurotoxin to the renal nerve of the patient. 40.The method of claim 24 wherein delivering a neuromodulatory agent to arenal nerve of a hypertensive human patient comprises delivering alcoholto the renal nerve of the patient.
 41. The method of claim 24 whereindelivering a neuromodulatory agent to a renal nerve of a hypertensivehuman patient comprises delivering phenol, ketamine, and/or anantidepressant to the renal nerve of the patient.
 42. The method ofclaim 24 wherein at least partially blocking neural activity along therenal nerve with the neuromodulatory agent comprises denervating akidney of the patient.
 43. The method of claim 24 wherein at leastpartially blocking neural activity along the renal nerve with theneuromodulatory agent comprises ablating the renal nerve via theneuromodulatory agent.
 44. The method of claim 24 wherein at leastpartially blocking neural activity along the renal nerve with theneuromodulatory agent further results in a reduction of systemicsympathetic tone in the patient.